1-Methylpyrrolidine → HCID 57717475, compound

HRID 2360560Notes

Reaction equation

HRID 2360560 reaction equation
C([CH:5]1[C:8]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7][NH:6]1)(C)(C)C.Cl[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=1.[CH3:25]CN(CC)CC.CC[O:34][C:35](C)=[O:36].CN1[CH2:43][CH2:42][CH2:41]C1>>[CH3:22][O:21][C:19]([C:18]1[CH:23]=[CH:24][C:15]([N:11]2[CH2:10][CH2:9][C:8]3([CH2:5][N:6]([C:35]([O:36][C:42]([CH3:41])([CH3:43])[CH3:25])=[O:34])[CH2:7]3)[CH2:13][CH2:12]2)=[N:16][CH:17]=1)=[O:20]

Participants

6

Reactant 5

HCID 84541-MethylpyrrolidineHCID 8471TriethylamineHCID 8857Ethyl AcetateHCID 254249Methyl 6-chloropyridine-3-carboxylateHCID 67104371HCID 67104371, compound

Product 1

HCID 57717475HCID 57717475, compound

Conditions

Temperature
180 °C

Procedure

A mixture of tert-butyl 2,7-diazaspiro[3.5]nonane (660 mg, 2.91 mmol), methyl 6-chloronicotinate (500 mg, 2.91 mmol) and Et3N (0.487 mL, 3.50 mmol) in 2 mL of N-methylpyrrolidine was stirred under microwave irradiation for 20 min at a temperature of 180° C. The mixture was poured into EtOAc and washed with sat'd NaHCO3, dried (MgSO4), filtered and concentrated, giving tert-butyl 7-[5-(methoxycarbonyl)pyridine-2-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate. The methyl ester was dissolved in 2 mL of 1:1 THF/water, treated with LiOH.H2O (26 mg, 0.62 mmol) and stirred for 20 hours. The mixture was poured into EtOAc and washed with 1M HCl followed by brine, dried (MgSO4), filtered and concentrated, providing 6-[2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]non-7-yl]nicotinic acid. A mixture of the carboxylic acid in 2 mL of DMF was treated with EDC (132 mg, 0.69 mmol), HOBt (93 mg, 0.69 mmol) and phenylenediamine (125 mg, 1.15 mmol), stirred for 15 h at room temperature. The reaction mixture was then diluted with EtOAc and washed with sat.'d NaHCO3, dried (MgSO4), filtered and concentrated. The crude oil was purified by reverse phase flash chromatography (10-100% MeCN/H2O with 0.05% TFA) and formation of the desired product, tert-butyl 7-(5-{[(2-aminophenyl)amino]carbonyl}pyridine-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate, which was confirmed by MS (ESI+): cal'd [M+H]+ 438.2, obs'd 438.3.

Workup

  1. washwashed with sat'd NaHCO3
  2. dry with materialdried (MgSO4)
  3. filtrationfiltered
  4. concentrationconcentrated

Sources & evidence

ORD record
ord-a55fd4b4f40644cf93582ab739cf49bf
Source dataset
uspto-grants-2014_04
Patent number
US08686020B2

Reaction notes

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